In vitro activity: Trapazamine (also known as SR-4233; SR259075; Win59075; SR4233) is an experimental adjuvant drug and a DNA-damaging agent that has the potential for the treatment of cervical carcinoma, head and neck cancer. Tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis when activated to its toxic form preferentially in the hypoxic areas of solid tumors. When combined with chemotherapeutic drugs such as Doxorubicin (DOX) and SN-38 (the active metabolite of irinotecan), trapazamine dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs.

Kinase Assay:

Cell Assay: in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs.